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Chewing and Swallowing Training in Coffin-Lowry Syndrome: A Case Report.
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Coffin-Lowry Syndrome (CLS) is a rare X-linked genetic disorder characterized by growth delays, facial dysmorphisms, and intellectual disabilities. Currently, there are limited published case reports regarding the anesthetic management of patients with CLS. Managing anesthesia for CLS patients can be complex due to difficult airway management. In this case report, we present a patient with CLS who underwent surgical intervention, highlighting the anesthetic considerations encountered throughout the perioperative period. We aim to summarize the difficulties involved in anesthetic management of rare conditions like CLS to improve clinical outcomes for affected individuals.
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Manejo de la Vía Aérea , Síndrome de Coffin-Lowry , Humanos , Manejo de la Vía Aérea/métodos , Síndrome de Coffin-Lowry/complicaciones , Masculino , Anestesia/métodosRESUMEN
BACKGROUND: Coffin-Lowry syndrome (CLS) is a rare X-linked condition with intellectual disability, growth retardation, characteristic facies and skeletal anomalies. To date, hypertriglyceridemia has not been reported in literature to be associated with CLS. CASE PRESENTATION: Herein, we report a case of very severe hypertriglyceridemia 32 mmol/L (2834 mg/dL) detected incidentally at three months old in an otherwise well boy born late preterm with intrauterine growth restriction, when he presented with lipaemic plasma. He was later diagnosed with CLS. No pathogenic mutations were found for hypertriglyceridemia, and no secondary causes could explain his very severe hypertriglyceridemia. CONCLUSIONS: The very severe hypertriglyceridemia in this case may appear to be a serious presentation of an unrecognised clinical feature of CLS, further expanding its phenotype.
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Síndrome de Coffin-Lowry , Hipertrigliceridemia , Discapacidad Intelectual , Masculino , Recién Nacido , Humanos , Lactante , Síndrome de Coffin-Lowry/complicaciones , Síndrome de Coffin-Lowry/diagnóstico , Síndrome de Coffin-Lowry/genética , Cara/patología , Discapacidad Intelectual/genética , Discapacidad Intelectual/complicaciones , Mutación , Hipertrigliceridemia/complicaciones , Hipertrigliceridemia/diagnósticoRESUMEN
Intellectual disability (ID) is a neurodevelopmental disorder associated with impaired cognitive and adaptive behaviors and represents a major medical issue. Although ID-patients develop behavioral problems and are diagnosed during childhood, most behavioral studies in rodent models have been conducted in adulthood, missing precocious phenotypes expressed during this critical time-window characterized by intense brain plasticity. Here, we selectively assessed postnatal ontogenesis of behavioral and cognitive processes, as well as postnatal brain development in the male Rsk2-knockout mouse model of the Coffin-Lowry syndrome, an X-linked disorder characterized by ID and neurological abnormalities. While Rsk2-knockout mice were born healthy, a longitudinal MRI study revealed a transient secondary microcephaly and a persistent reduction of hippocampal and cerebellar volumes. Specific behavioral parameters from postnatal day 4 (P4) unveiled delayed acquisition of sensory-motor functions and alterations of spontaneous and cognitive behaviors during adolescence, which together, represent hallmarks of neurodevelopmental disorders. Together, our results suggest for the first time that RSK2, an effector of the MAPK signaling pathways, plays a crucial role in brain and cognitive postnatal development. This study also provides new relevant measures to characterize postnatal cognitive development of mouse models of ID and to design early therapeutic approaches.
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Síndrome de Coffin-Lowry , Discapacidad Intelectual , Animales , Ratones , Masculino , Discapacidad Intelectual/genética , Encéfalo , Cognición , Síndrome de Coffin-Lowry/genética , Modelos Animales de Enfermedad , Ratones NoqueadosRESUMEN
Coffin-Lowry syndrome (CLS, OMIM # 303600) is a rare X-linked disorder caused by mutations in RPS6KA3. CLS is characterized by facial dysmorphism, digit abnormalities, developmental delays, growth retardation, and progressive skeletal changes in male patients. Females with CLS are variably affected, complicating diagnosis. Here, we describe the clinical and molecular findings in a female Korean child with CLS and review the associated literature. A 5-year-old girl presented with short stature and developmental delays. She had a coarse facial appearance characterized by a prominent forehead, hypertelorism, thick lips, and hypodontia. She also had puffy tapering fingers and pectus excavatum. We performed exome sequencing and identified a novel, likely pathogenic, heterozygous variant, c.326_338delinsCTCGAGAC (p.Val109Alafs*10), in RPS6KA3 (NM_004586.2). This is the first Korean female genetically diagnosed with CLS. In contrast to the delayed bone age reported in previous studies, our patient showed advanced bone age and central precocious puberty. CLS should be considered as a differential diagnosis of short stature, tapering fingers, and developmental delay. We suggest that molecular techniques can be a useful tool for diagnosis of rare disorders such as CLS because such conditions are not simple, and the associated spectrum of phenotypes can vary.
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Background: Coffin-Lowry syndrome (CLS) [OMIM#303600] is a rare X-linked dominant syndrome. CLS is caused by highly heterogeneous loss-of-function mutations in the RPS6KA3 gene (OMIM*300,075). CLS is characterized by intellectual disability (ID), short stature, tapered fingers, characteristic facial features, and progressive skeletal changes. Distal 22q11.2 microdeletion syndrome (OMIM#611867) is an autosomal dominant and recurrent genomic disorder. It mainly includes three types [distal type I (D-E/F), type II (E-F), and type III (F-G)] and exhibits variable clinical phenotypes (mild, moderate, or even normal): preterm birth, pre- and/or postnatal growth restriction, development delay, ID, behavioral problems, cardiovascular defects, skeletal anomalies, and dysmorphic facial features. We investigated the genetic etiology of a Chinese pedigree with ID, short stature, digit abnormalities, facial dysmorphism, and menstrual disorder. A heterozygous RPS6KA3 gene variant c.898C>T (p.R300X) was identified in this familial case. Two female CLS patients with distal 22q11.2 microdeletion presented with more severe clinical phenotypes. We provided clinical characteristics of these Chinese female CLS patients. Case presentation: We described a Chinese family with three affected females (the mother, the elder sister, and the proband). The mother and the elder sister had more severe clinical phenotypes (moderate facial dysmorphism, more severe cognitive impairment, and shorter stature). The common characteristic phenotypes are ID, short stature, facial dysmorphism, irregular menstruation, and cardiovascular disorders. Peripheral blood samples were collected from the pedigree. Whole-exome sequencing (WES) identified a heterozygous nonsense RPS6KA3 gene variant c.898C>T (p.R300X). It was verified by Sanger sequencing. Copy number variation sequencing (CNV-seq) showed that both the mother and the elder sister carried a CNVseq [hg19] del (22) (q11.22-q11.23) (22997582-23637176)×0.5. RNA from peripheral blood samples was used for measuring the relative quantification of mRNA (expressed by exon 14 of RPS6KA3). The levels of mRNA relative expressions were significantly lower in the mother's and the elder sister's blood samples. The levels of mRNA relative expressions were significantly higher in the proband's blood sample. X-chromosome inactivation (XCI) studies demonstrated that the proband showed extremely skewed XCI, and the XCI pattern of the elder sister was random. Conclusion: Herein, we reported three Chinese female patients with a heterozygous nonsense RPS6KA3 gene variant c.898C>T. Further genetic studies were performed. To our knowledge, Chinese patients with this variant have not been previously reported in the literature. The three female patients presented with variable degrees of severity. The clinical characteristics of these Chinese female CLS patients could expand the phenotypic spectrum of CLS. We helped physicians to understand the genotype-phenotype correlation further.
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Coffin-Lowry syndrome is a rare X-linked disorder that shows a varied clinical presentation. We report cardiac involvement, particularly abnormalities of mitral valve morphology, in a 14-year-old male adolescent with a known diagnosis of Coffin-Lowry syndrome, who presented with easy fatigability. Echocardiography revealed severe mitral and moderate tricuspid regurgitation, and the papillary muscles were attached to the base of the left ventricle. We performed tricuspid annuloplasty and mitral valve repair using two artificial chordae and a semi-rigid full ring. The patient's postoperative course was uneventful. Postoperative echocardiography revealed reduced mitral regurgitation, and his cardiac failure improved.
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Anuloplastia de la Válvula Cardíaca , Síndrome de Coffin-Lowry , Anuloplastia de la Válvula Mitral , Insuficiencia de la Válvula Mitral , Insuficiencia de la Válvula Tricúspide , Adolescente , Humanos , Masculino , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/cirugía , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/cirugía , Resultado del Tratamiento , Válvula Tricúspide/diagnóstico por imagen , Válvula Tricúspide/cirugía , Insuficiencia de la Válvula Tricúspide/diagnóstico por imagen , Insuficiencia de la Válvula Tricúspide/cirugíaRESUMEN
Background and objectives: Coffin-Lowry Syndrome (CLS), a rare neurodegenerative disorder, is mainly diagnosed based on clinical manifestations and molecular analyses. In total, about 20 cases of CLS have been reported in China. Here, we report two cases of CLS in identical twin brothers and examine their potential causative mutations. Methods: The Trio mode was used in this analysis, i.e., DNA from the proband and his parents was sequenced. Furthermore, DNA from the proband's twin brother was used for confirmation. Results: A hemizygous variation was detected in the 11th exon of the RPS6KA3 gene, c.898C>T (p.R300*) of the proband, and the same site variation was detected in his identical twin brother; however, the mutation was not detected in his parents. Conclusions: The RPS6KA3 gene mutation c.898C>T (p.R300*) is the causative factor of familial CLS. The variant detected was reported for the first time in the Chinese population. Additionally, by analyzing the previous literature, we were able to summarize the phenotypic and genetic characteristics of GLS in China.
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Síndrome de Coffin-Lowry , Síndrome de Coffin-Lowry/diagnóstico , Síndrome de Coffin-Lowry/genética , Exones , Humanos , Masculino , Mutación , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , HermanosRESUMEN
BACKGROUND: Coffin-Lowry syndrome (CLS) is a syndromic form of X-linked intellectual disability, in which specific associated facial, hand, and skeletal abnormalities are diagnostic features. METHODS: In the present study, an unreported missense genetic variant of the ribosomal S6 kinase 2 (RSK2) gene has been identified, by next-generation sequencing, in two related males with two different phenotypes of intellectual disability (ID) and peculiar facial dysmorphisms. We performed functional studies on this variant and another one, already reported in the literature, involving the same amino acid residue but, to date, without an efficient characterization. RESULTS: Our study demonstrated that the two variants involving residue 189 significantly impaired its kinase activity. CONCLUSIONS: We detected a loss-of-function RSK2 mutation with loss in kinase activity in a three-generation family with an X-linked ID.
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We report a Japanese girl with Coffin-Lowry syndrome phenotype such as hypertelorism, hypodontia, and tapering fingers and 46,XX,t(X;11)(p22;p15)dn. Whole genome sequencing revealed RPS6KA3 disruption by the translocation, and X-inactivation analysis indicated preferential inactivation of the normal X chromosome. The results explain the development of an X-linked disease in this girl.
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Coffin-Lowry syndrome (CLS) is a rare X-linked disorder characterized by moderate to severe intellectual disability, hypotonia, craniofacial features, tapering digits, short stature, and skeletal deformities. Using whole exome sequencing and high-resolution targeted comparative genomic hybridization array analysis, we identified a novel microduplication encompassing exons five through nine of RPS6KA3 in three full brothers. Each brother presented with intellectual disability and clinical and radiographic features consistent with CLS. qRT-PCR analyses performed on mRNA from the peripheral blood of the three siblings revealed a marked reduction of RPS6KA3 levels suggesting a loss-of-function mechanism. PCR analysis of the patients' cDNA detected a band greater than expected for an exon 4-10 amplicon, suggesting this was likely a direct duplication that lies between exons 4 through 10, which was later confirmed by Sanger sequencing. This microduplication is only the third intragenic duplication of RPS6KA3, and the second and smallest reported to date thought to cause CLS. Our study further supports the clinical utility of methods such as next-generation sequencing and high-resolution genomic arrays to detect small intragenic duplications. These methods, coupled with expression studies and cDNA structural analysis have the capacity to confirm the diagnosis of CLS in these rare cases.
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Duplicación Cromosómica , Síndrome de Coffin-Lowry/diagnóstico , Síndrome de Coffin-Lowry/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Hermanos , Niño , Facies , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Mutación , Linaje , FenotipoRESUMEN
Coffin-Lowry syndrome (CLS) is a well-described syndrome characterized by intellectual disability, growth retardation, recognizable dysmorphic features, and skeletal changes. It is an X-linked syndrome where males are more severely affected and females have high variability in clinical presentations. This case series reports nine molecularly confirmed Chinese CLS patients from six unrelated families (three with familial variants and three with de novo variants). There is a wide genotypic spectrum with five novel variants in RPS6KA3 gene. Clinical phenotype and facial features of these Chinese CLS patients are comparable to what has been described in other ethnicities.
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Pueblo Asiatico/genética , Síndrome de Coffin-Lowry/genética , Familia , Femenino , Genotipo , Humanos , Masculino , Linaje , FenotipoRESUMEN
Loss of function mutations in the rsk2 gene cause Coffin-Lowry syndrome (CLS), which is associated with multiple symptoms including severe mental disabilities. Despite the characterization of ribosomal S6 kinase 2 (RSK2) as a protein kinase acting as a downstream effector of the well characterized ERK MAP-kinase signaling pathway, it turns out to be a challenging task to link RSK2 to specific neuronal processes dysregulated in case of mutation. Animal models such as mouse and Drosophila combine advanced genetic manipulation tools with in vivo imaging techniques, high-resolution connectome analysis and a variety of behavioral assays, thereby allowing for an in-depth analysis for gene functions in the nervous system. Although modeling mental disability in animal systems has limitations because of the complexity of phenotypes, the influence of genetic variation and species-specific characteristics at the neural circuit and behavioral level, some common aspects of RSK2 function in the nervous system have emerged, which will be presented. Only with this knowledge our understanding of the pathophysiology of CLS can be improved, which might open the door for development of potential intervention strategies.
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Endogenous molecular circadian clocks drive daily rhythmic changes at the cellular, physiological, and behavioral level for adaptation to and anticipation of environmental signals. The core molecular system consists of autoregulatory feedback loops, where clock proteins inhibit their own transcription. A complex and not fully understood interplay of regulatory proteins influences activity, localization and stability of clock proteins to set the pace of the clock. This study focuses on the molecular function of Ribosomal S6 Kinase (RSK) in the Drosophila melanogaster circadian clock. Mutations in the human rsk2 gene cause Coffin-Lowry syndrome, which is associated with severe mental disabilities. Knock-out studies with Drosophila ortholog rsk uncovered functions in synaptic processes, axonal transport and adult behavior including associative learning and circadian activity. However, the molecular targets of RSK remain elusive. Our experiments provide evidence that RSK acts in the key pace maker neurons as a negative regulator of Shaggy (SGG) kinase activity, which in turn determines timely nuclear entry of the clock proteins Period and Timeless to close the negative feedback loop. Phosphorylation of serine 9 in SGG is mediated by the C-terminal kinase domain of RSK, which is in agreement with previous genetic studies of RSK in the circadian clock but argues against the prevailing view that only the N-terminal kinase domain of RSK proteins carries the effector function. Our data provide a mechanistic explanation how RSK influences the molecular clock and imply SGG S9 phosphorylation by RSK and other kinases as a convergence point for diverse cellular and external stimuli.
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BACKGROUND: Coffin-Lowry syndrome is a rare X-linked disease, caused by loss-of-function mutations in the RPS6KA3 gene. Patients exhibit severe intellectual disability with characteristic dysmorphism. As there are no specific laboratory findings to support the diagnosis of Coffin-Lowry syndrome, it may be difficult to diagnose-especially in young children, where the characteristic craniofacial features are less discernible. CASE: Here we report on a 2-year-old boy with Coffin-Lowry syndrome with a novel missense mutation in the RPS6KA3 gene. On magnetic resonance imaging, his brain exhibited periventricular signal abnormalities with multiple small cystic lesions. These findings may aid in diagnosis of Coffin-Lowry syndrome.
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Encéfalo/diagnóstico por imagen , Síndrome de Coffin-Lowry/diagnóstico , Síndrome de Coffin-Lowry/genética , Mutación Missense , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Preescolar , Síndrome de Coffin-Lowry/patología , Diagnóstico Diferencial , Cara/anomalías , Humanos , Imagen por Resonancia Magnética , Masculino , FenotipoRESUMEN
PURPOSE: Little is known about the natural history of spinal deformities in Coffin-Lowry syndrome (CLS). Our goal was to evaluate the spinal deformity progression and clinical impact. METHODS: In this institutional review board-approved study, we performed a multinational retrospective review of six male CLS patients, aged 13 to 22 years at final follow-up, for a mean of 7.25 years (3 to 13). RESULTS: All showed delayed skeletal maturity. Three had calcifications of their lower cervical ligamentum flavum, all experienced neural axis abnormalities, including lower extremity weakness, numbness and tingling and in one, quadriparesis. Only two were ambulatory at final follow-up.All had significant spinal abnormalities, including severe progressive thoracic lordosis, thoracolumbar kyphosis and scoliosis. All had undergone spinal fusion or were being evaluated for surgery. CONCLUSION: CLS is a rare X-linked mutation in the RSK2 gene, affecting between 1/50 000 to 100 000 people. There are two reports in the literature of patients with calcifications of their ligamentum flavum. Both had neural axis abnormalities and one had acute onset quadriplegia. Analysis of their ligamentum flavum found abundant central calcifications. Despite our small cohort we found 50% had calcifications and 100% had neurologic consequences associated with those calcifications. There was a 100% rate of deformity progression.They all exhibited delay in skeletal maturity, which mandates longer follow-up and has implications for surgical planning.From our cohort and literature review, the natural history of CLS supports frequent patient evaluation and a lower threshold for correction of spinal deformities. Aiming to avoid spinal cord compression and improve or avoid neurological deterioration. LEVEL OF EVIDENCE: IV - retrospective study.
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Ribosomal s6 kinase 2 is a growth factor activated serine/threonine kinase and member of the ERK signaling pathway. Mutations in the Rsk2 gene cause Coffin-Lowry syndrome, a rare syndromic form of intellectual disability. The Rsk2 KO mouse model was shown to have learning and memory defects. We focused on the investigation of the emotional behavioral phenotype of Rsk2 KO mice mainly in the IntelliCage. They exhibited an anti-depressive, sucrose reward seeking phenotype and showed reduced anxiety. Spontaneous activity was increased in some conventional tests. However, KO mice did not show defects in place learning, working memory and motor impulsivity. In addition, we found changes of the monoaminergic system in HPLC and qRT-PCR experiments. Taken together, RSK2 not only plays a role in cognitive processes but also in emotional and reward-related behaviors.
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Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Animales , Ansiedad/genética , Síndrome de Coffin-Lowry/genética , Depresión/genética , Modelos Animales de Enfermedad , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Ratones Noqueados , FenotipoRESUMEN
Coffin-Lowry syndrome (CLS) is a rare genetic disorder inherited in an X-linked dominant pattern. Common manifestations include intellectual disability, growth retardation, dysmorphic facial features, and variable skeletal anomalies. Here we report a patient who first presented with episodes of apparent life-threatening events (ALTE) found to be caused by hydrocephalus and brainstem compression at the foramen magnum. Together with his small size, short limbs and fingers, and facial appearance, the narrowing of the foramen magnum lead to the initial clinical misdiagnosis of hypochondroplasia. Subsequent evaluation and testing lead to the correct diagnosis of CLS. This case demonstrates the variability in presentation of CLS, and that skeletal findings may be misleading in infancy. © 2017 Wiley Periodicals, Inc.
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Cromosomas Humanos X/química , Síndrome de Coffin-Lowry/diagnóstico , Foramen Magno/anomalías , Hidrocefalia/diagnóstico , Mutación Puntual , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Huesos/anomalías , Huesos/patología , Síndrome de Coffin-Lowry/genética , Síndrome de Coffin-Lowry/patología , Síndrome de Coffin-Lowry/cirugía , Diagnóstico Diferencial , Enanismo/diagnóstico , Enanismo/patología , Exoma , Foramen Magno/inervación , Foramen Magno/cirugía , Expresión Génica , Genes Dominantes , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hidrocefalia/genética , Hidrocefalia/patología , Hidrocefalia/cirugía , Lactante , Deformidades Congénitas de las Extremidades/diagnóstico , Deformidades Congénitas de las Extremidades/patología , Lordosis/diagnóstico , Lordosis/patología , Imagen por Resonancia Magnética , MasculinoRESUMEN
RESUMO Descrevemos paciente de 27 anos com síndrome de Coffin-Lowry, com quadro de pneumonia comunitária grave, choque séptico e insuficiência respiratória. Sumarizamos a assistência ventilatória mecânica, bem como o período de internação em unidade de terapia intensiva.
ABSTRACT We describe a 27-year-old patient with Coffin-Lowry syndrome with severe community pneumonia, septic shock and respiratory failure. We summarize both the mechanical ventilatory assistance and the hospitalization period in the intensive care unit.